A new regulatory mechanism of NF-kappaB activation by I-kappaBbeta in cancer cells.
Transglutaminase 2 (TGase 2) catalyzes covalent isopeptide bond formation between glutamine and lysine residues. Recently, we reported that TGase 2 activates nuclear factor-kappa B (NF-kappaB) by depleting inhibitor of NF-kappaBalpha (I-kappaBalpha) levels via polymer formation. Furthermore, TGase 2 expression synergistically increases NF-kappaB activity with canonical pathway. The major I-kappaB proteins such as I-kappaBalpha and I-kappaBbeta resemble each other in both primary sequence and tertiary structure. However, I-kappaBbeta does not degrade fully, while I-kappaBalpha degrades immediately in response to most stimuli. We found that I-kappaBbeta does not contain any of the previously identified TGase 2 target sites. In this study, both an in vitro cross-linking assay and a TGase 2 transfection assay revealed that I-kappaBbeta is independent from TGase 2-mediated polymerization. Furthermore, increased I-kappaBbeta expression reversed NF-kappaB activation in cancer cells, compensating for the loss of I-kappaBalpha via TGase 2 polymerization.
Kim
Jung Mo
JM
Molecular Oncology Branch, Division of Basic and Applied Sciences, Research Institute, National Cancer Center, Ilsandong-Gu, Goyang, Gyeonggi-Do, Republic of Korea.
Voll
Reinhard E
RE
Ko
Chunkyu
C
Kim
Dae-Seok
DS
Park
Kang-Seo
KS
Kim
Soo-Youl
SY
D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D016415:Sequence Alignment; D011503:Transglutaminases / Q000378:metabolism
C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins